Cyclopropanones substituted

A significant step in studying the chemistry of cyclopropanones has resulted from the discovery that many labile carbonyl derivatives such as hemiacetals and carbinol amines are useful precursors of the parent ketone. 4-6> Such derivatives may be isolated, purified and used as cyclopropanone substitutes or, alternatively, may be generated in solution and used as in situ precursors. As a result of these advances, exploration of cyclopropanone chemistry has recently been accelerated. The aim of this article is to review some of this chemistry, noting areas where there may be potential applications in synthesis. 

In the initial step " the a-halo ketone 1 is deprotonated by the base at the a -carbon to give the carbanion 4, which then undergoes a ring-closure reaction by an intramolecular substitution to give the cyclopropanone derivative 2. The halogen substituent functions as the leaving group ... 

Nucleophilic addition of the base to the intermediate 2 leads to ring opening. With a symmetrically substituted cyclopropanone, cleavage of either Ca-CO bond leads to the same product. With unsymmetrical cyclopropanones, that bond is broken preferentially that leads to the more stable carbanion 5 ... 

Ethenylcyclopropyl tosylates 131 and 2-cyclopropylideneethyl acetates 133, readily available from the cyclopropanone hemiacetals 130, undergo the re-gioselective Pd(0)-catalyzed nucleophilic substitution via the unsymmetrical 1,1-dimethylene-jr-allyl complexes. For example, reduction with sodium formate affords a useful route from 131 to the strained methylenecyclopropane derivatives 132. The regioselective attack of the hydride is caused by the sterically... 

Semiempirical calculations have been used to study the mechanism of the ring opening of cyclopropanone and substituted analogues in a range of solvents of varying polarity. Transition states and oxyallyl intermediates have been characterized, as have the effects of solvents on their stability. The results are also compared with kinetic data in the literature. 

Thus the cyclopropanone hydrate 21 is an inhibitor of yeast aldehyde dehydrogenase (ALDH) through the nucleophilic substitution of a hydroxyl group by an enzymic thiol 47 leading to the cyclopropanone hemithioacetal 24 a, Eq. (16) [211. 

Allylzincation of the monosubstituted cyclopropenone ketal 137 with the chiral reagent 138 proceeded regioselectively so as to generate the less substituted secondary cyclo-propylzinc species 139. After hydrolysis, the resulting cyclopropanone ketal was obtained with high enantiomeric excess ( = 99%). The reaction was very slow at 20 °C but was considerably accelerated under high pressure (1 GPa) (equation 67)102. 

Besides the activation of the olefinic partner by a metal, the unfavorable thermodynamics associated with the addition of an enolate to a carbon—carbon multiple bond could be overwhelmed by using a strained alkene such as a cyclopropene derivative286. Indeed, Nakamura and workers demonstrated that the butylzinc enolate derived from A-methyl-5-valerolactam (447) smoothly reacted with the cyclopropenone ketal 78 and subsequent deuterolysis led to the -substituted cyclopropanone ketal 448, indicating that the carbometallation involved a syn addition process. Moreover, a high level of diastereoselectivity at the newly formed carbon—carbon bond was observed (de = 97%) (equation 191). The butylzinc enolates derived from other amides, lactams, esters and hydrazones also add successfully to the strained cyclopropenone ketal 78. Moreover, the cyclopropylzincs generated are stable and no rearrangements to the more stable zinc enolates occur after the addition. 

The most common reaction involving this type of cycloaddition is the reaction of ketenes with diazoalkanes (Houben-Weyl, Vol. 4/4, pp 406-408) which proceed via cyclopropanone intermediates. This type of reaction finds limited use due to nonregioselective formation of substituted cyclobutanones as mixtures. 

Using diazomethane as the limiting reagent, silyl- and germyl-substituted ketenes5-7 in certain cases gave cyclopropanones which were isolated as stable compounds.5,6 Transformations of trimethylsilylketene and triethylgermylkelene to the 2- and 3-substituted cyclobutanones was accomplished in 90 and 82% yield, respectively. Mild reaction conditions (— 78 °C) in diethyl ether solutions were employed. 

In situ ring enlargement of intermediate cyclopropanones to silyl- and germyl-substituted cyclobutanones was achieved by treatment of silyl- and germyl-substituted ketenes 12 with an excess of diazomethane.129,130... 

Mono- and bis(trimethylsilyl)-substituted cyclopropanones 15 are stable enough to be isolated. Reaction with diazomethane,131 trimethylsilyldiazomethane131 and diazoacetic acid es-ters 130 131 yielded mono-, bis- and tris(trimethylsilyl)-subslitutcd cyclobutanones 16 and 17. In all cases, the regio- and stereochemistry arc in accord with the general rules given. 

It should be noted that in this case either of the carbonyl-carbon bonds in the symmetrical intermediate cyclopropanone system could be cleaved. With unsymmetrically substituted cyclic ketones (or indeed open chain ketones), the direction of cleavage is that which would lead to the more stable carbanion. 

A versatile synthesis of cyclopropanones and closely related derivatives is provided by the diazoalkane-ketene reaction as shown in Scheme 2. Using this method, the parent ketone 2>3> and alkyl-substituted cyclopropanones 1()) have been prepared in yields of 60—90% based upon the concentration of diazoalkaneb) (Table 2). The reaction is rapid at Dry Ice-acetone temperatures and is accompanied by evolution of nitrogen. Although most cyclopropanones are not isolable, dilute solutions of 3 (0.5—0.8 M) may be stored at — 78 °C for several days or at room temperature in the presence of suitable stabilizing agents.15) The hydrate and hemiketal derivatives are readily prepared by the addition of water or alcohols to the solutions of. .2>8>5)... 

As shown in Table 2, the application of this method to the synthesis of aryl-substituted cyclopropanones 16> and cyclopropanone acetals 17>18> has been moderately successful, although products other than the expected ketones may be obtained. For example, the oxadiazoline 4 and not tetraphenylcyclopropanone is formed when diphenylketene is allowed to react with diphenyldiazomethane.19>... 

The reaction of carbenes with appropriately substituted olefins provides a useful method for the preparation of many cyclopropanone derivatives. The Simmons-Smith procedure 22> and reactions involving base-generated carbenes, e.g. CHC13/KO-7-Bu, are particularly useful. 

Further analysis of the microwave spectra provides a precise description of the bond lengths and angles (Table 7). The C2C3 bond is unusually long and relatively weak as shown by the reactivity of substituted cyclopropanones in cycloaddition reactions (see Section 4.4). The carbon-oxygen bond is somewhat shorter than the average carbonyl group and this feature is reflected in the infrared properties of cyclopropanones outlined below. 

Cyclopropanones react with ammonia and aliphatic amines to form carbinol amines which usually undergo further amine substitution. For example, attempts to prepare the carbinol amines f> from dimethylamine and cyclopropanone resulted only in the isolation of the 1,1-diamino derivative 94. 86> When methyl amine is added to cyclopropanone, the... 

Table 11. 1-Substituted cyclopropanols from Grignard addition to cyclopropanone...

Other alkylation reactions are observed in the condensation of cyclo-propanium ions (generated in situ) with ketones 89.92)> enamines6, nitroalkanes 93>, dimethylmalonate 92>, and phenol. 92> Thus, 7-hydroxy-7-pyrrolidinobicyclo[4.1.0]heptane (56) as well as the 7,7-dipyrrolidino derivative (54) react with acetone to give the amino ketone 113. 89> This reaction may be pictured as an addition of the enol form of the ketone to the reactive iminium salt formed from the carbinol amine. In like manner, phenol undergoes ortho substitution with the carbinol amine 114 formed from cyclopropanone and dimethyl amine. 

It appears that this route to cyclobutanones is applicable only to the most stable as well as the most favorably substituted cyclopropanones. 

An extension of this reaction leading to a general synthesis of N-substituted (3-lactams involves the addition of a primary amine to a freshly prepared solution of cyclopropanone, conversion of the resulting carbinol amine to the N-chloro derivative, and then decomposition of this intermediate with silver ion in acetonitrile. 87a> The method permits one to prepare N-substituted (3-lactams of great variety (Table 14), including those constructed from amino acid esters. 87b The use of valine ethyl ester (123) as a nitrogen source leading to 124 is illustrated. 

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